The aims of this proposal are to seek out novel interactions between the muscarinic receptor and receptors for other neurotransmitters and peptides within the brain. A likely mechanism for such interactions is the activation of protein kinase C by muscarinic receptors followed by phosphorylation of adenylate cyclase by protein kinase C. Consequently, the ability of muscarinic agonists to potentiate or modulate the effects which other neurotransmitters, drugs and peptides have on cyclic AMP accumulation in a variety of intact cell preparations from brain and peripheral tissues will be investigated. The potentially confounding effect of direct inhibition of adenylate cyclase by muscarinic receptors via the inhibitory guanine nucleotide binding protein will be eliminated by first pretreating tissue with pertussis toxin or by taking advantage of differences in the coupling of subtypes of the muscarinic receptor to phosphoinositide hydrolysis and inhibition of adenylate cyclase. The pharmacological characteristics of the subtypes of the muscarinic receptor responsible for activation of phosphoinositide hydrolysis and inhibition of adenylate cyclase will be defined in identical preparations of the corpus striatum and parotid gland by using pharmacological null methods and radioligand binding methods to analyze the pharmacological effects of selective muscarinic agonists and antagonists. In addition, the subtype of the muscarinic receptor involved in cross-talk with receptors that influence adenylate cyclase will be defined using similar methods. Finally, the mechanisms by which various drugs of psychopharmacological interest (neuroleptics, tricyclic antidepressants, lithium) interfere with muscarinic receptor coupling mechanisms will be investigated. The results of these studies are likely to be significant in revealing new cholinergic mechanisms within the brain which may be compromised in Alzheimer's disease and in other mental disorders associated with cholinergic hypofunction. Moreover, these results should provided insight into the development of more selective psychopharmacological agents and muscarinic agonists and antagonists.
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